Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity.
Normal brain function requires that the overall synaptic activity in neural circuits be kept constant. Long-term alterations of neural activity lead to homeostatic regulation of synaptic strength by a process known as synaptic scaling. The molecular mechanisms underlying synaptic scaling are largely unknown. Here, we report that all-trans retinoic acid (RA), a well-known developmental morphogen, unexpectedly mediates synaptic scaling in response to activity blockade. We show that activity blockade increases RA synthesis in neurons and that acute RA treatment enhances synaptic transmission. The RA-induced increase in synaptic strength is occluded by activity blockade-induced synaptic scaling. Suppression of RA synthesis prevents synaptic scaling. This form of RA signaling operates via a translation-dependent but transcription-independent mechanism, causes an upregulation of postsynaptic glutamate receptor levels, and requires RARalpha receptors. Together, our data suggest that RA functions in homeostatic plasticity as a signaling molecule that increases synaptic strength by a protein synthesis-dependent mechanism.
Aoto
Jason
J
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720-3200, USA.
Nam
Christine I
CI
Poon
Michael M
MM
Ting
Pamela
P
Chen
Lu
L
D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D014176:Protein Biosynthesis / Q000235:genetics; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C000607073:Rara protein, rat